tbuckley/cabot-search huggingface dataset:
Remission of peanut allergy is associated with rewiring of allergen‐driven T helper 2‐related gene networks
Authors: Sarah E. Ashley, Anya C. Jones, Denise Anderson, Patrick G. Holt, Anthony Bosco, Mimi L. K. Tang
Journal: Allergy (2022)

The immunological changes underpinning acquisition of remission (also called sustained unresponsiveness) following food immunotherapy remain poorly defined. Limited access to effective therapies and biosamples from treatment responders has prevented progress. Probiotic peanut oral immunotherapy is highly effective at inducing remission, providing an opportunity to investigate immune changes.Using a systems biology approach, we examined gene co-expression network patterns in peanut-specific CD4+ T cell responses before and after probiotic and peanut oral immunotherapy in subjects enrolled in the PPOIT-001 randomized trial: Responders who attained remission (n = 16), placebo-treated who remained allergic (n = 16).Acquisition of remission was associated with rewiring of gene network patterns, which was characterized by integration of T helper 2 and interferon signalling modules, markedly reduced T helper 2 gene connectivity, and shutdown in co-expression activity between T helper 2 effectors and cell cycle regulators.The immunological changes underlying remission following peanut oral immunotherapy are mediated by reprogramming of T helper 2-associated gene networks in the CD4+ T cell compartment. Findings provide insight into immune mechanisms driving the acquisition of remission following oral immunotherapy, paving the way for the development of improved approaches to induce remission/sustained unresponsiveness in patients with food allergy.
ETMR-07. DNA methylation profiling of a series of rare CNS embryonal tumors in children: diagnostic and clinical impact
Authors: Vito Andrea Dell’Anna, Stefano Gabriele Vallero, Franca Fagioli, Paola Peretta, Paola Cassoni, Luca Bertero
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: CNS embryonal tumors are a clinically and biologically heterogeneous group of tumors, more frequently arising in very young children. In the last few years, tumor classification through DNA methylation profiling has been demonstrated to be a powerful diagnostic tool which could be especially informative in this setting. METHODS: We reviewed original diagnosis and molecular profile of childhood CNS embryonal tumors other than medulloblastoma or AT/RT from a retrospective single-center cohort. Sixteen FFPE tissue samples from 14 unique patients (diagnosed from 1996 to 2017) were analyzed using DNA methylation arrays and matched with the Heidelberg classifier. Then, cohort characteristics and outcome were re-evaluated according to the results of the array. RESULTS: Median age at diagnosis was 2.7 years; there was no statistically significant difference between ETMRs and CNS embryonal tumors, NOS. Male to female ratio was 4:3. Median OS was 17,5 months (IQR 10.2-103.3 months) and ETMRs presented the worst outcome. Methylation profiling matched with an adequate score in 50% of samples (8/16). DNA methylation profile was consistent with ETMR in two samples but only one showed amplification of C19MC. Seven CNS embryonal tumors, NOS were properly reclassified as supratentorial ependymoma and diffuse pediatric-type HGG (4 and 1) or better defined as CNS neuroblastoma, FOXR2-altered (2). Methylation profiling added a unique diagnostic contribution in 64.3% of all cases (9/14). After the integration of methylation array results, survival markedly differed according to the novel integrated diagnoses; supratentorial ependymomas presented the longest median OS while no patients refined as CNS neuroblastoma or HGG survived. CONCLUSIONS: Our study confirmed that DNA methylation profiling provides relevant information for the classification of rare neoplasms like CNS embryonal tumors. Especially for selected cases with ambiguous histology, implementation of this tool should be considered to improve diagnostic precision and tailor patients’ management.
Race-specific genomic determinants of therapeutic response in African American NSCLC patients.
Authors: Amanda Pilling, Pin Li, Kaitlyn Kane, Frank M. Wolf, Anna B. Berry, Shirish M. Gadgeel
Journal: Journal of Clinical Oncology (2022)

e21015 Background: African American (AA) individuals are disproportionately affected by lung cancer in terms of incidence and mortality, despite lower tobacco exposure compared to Caucasian Americans (CA). Since molecular profiling is critically important to guide therapy selection in non-small cell lung cancer (NSCLC), we compared treatment-relevant molecular data in a cohort of AA and CA patients with EGFR or KRAS-driven NSCLC. Methods: This is a retrospective study using a clinicogenomic electronic medical record database from health systems in the United States designed to evaluate outcomes in advanced stage NSCLC. Eligibility criteria for analysis included a diagnosis of NSCLC between 2010 and 2020, stage III or IV, available race/ethnicity data, and identification of common KRAS or EGFR activating variant within 60 days of diagnosis. The primary objective was to define the type of EGFR or KRAS activating variant and determine the frequency of co-occurring alterations in NSCLC-associated genes by cohort (AA and CA). Secondary objectives included examining the timing of genetic testing and use of targeted therapy in these cohorts. Results: A total of 642 NSCLC patients with KRAS (15.0% AA; 81.6% CA) and 348 patients with EGFR oncogenic mutations (13.8% AA; 70.1% CA) met inclusion criteria. Mean time from diagnosis to first molecular test result was 20.9 days for AA vs. 19.9 days for CA (p = 0.5). The EGFR G719S variant was more prevalent in the AA cohort (6.3% AA v 0.4%) with no significant differences observed in the most common KRAS or EGFR variants tested (Table). A total of 100 KRAS-mutant patients (16 AA, 86 CA) had a reported result in at least one co-mutation of interest. The most frequent co-mutations were TP53 (81.3% AA v 65% CA, p = 0.92); KEAP1 (18.8% AA v 8.3% CA, p = 0.52); ATM (18.8% AA v 9.5% CA, p = 0.54); and PTEN (0% AA v 8.3% CA, p = 0.5). A total of 35 EGFR-mutant patients (4 AA, 31 CA) had a co-mutation reported in TP53 (75% AA v 65% CA, p = 0.77). EGFR targeted therapy was reported in 47.9% of AA and 52.9% of CA (p = 0.639). In the KRAS-mutant cohort, delivery of immune checkpoint inhibitors (ICIs) was reported in 29.2% of AA and 39.3% of CA (p = 0.08); chemotherapy was reported in 36.5% AA and 45.2% of CA (p = 0.14). Delivery of both ICI and chemotherapy was reported in 13.5% of AA and 21.9% of CA (p = 0.08). Conclusions: In a real-world cohort of NSCLC patients, we found similar frequencies of common KRAS and EGFR variants in AA and CA, but higher rates of EGFR G719S variant in AA patients. A more comprehensive analysis is needed to further evaluate the trends in co-mutations observed in our analysis, to determine the race-specific impact of these alterations in EGFR and KRAS-driven NSCLC.[Table: see text]
RONC-12. Evaluation of brain network segregation using resting state functional MRI in pediatric brain tumor patients treated with proton beam therapy
Authors: Anna Dowling, Benjamin Seitzman, Timothy Mitchell, Michael Olufawo, Miriam Agamah, Rachel Butler, Alana McMichael, Donna Dierker, Hari Anandarajah, Ally Dworetsky, Rebecca Coalson, Catherine Jiang, Hongjie Gu, Dennis Barbour, Bradley Schlaggar, David Limbrick, Jennifer Strahle, Joshua Rubin, Joshua Shimony, Stephanie Perkins
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Mechanisms of cognitive injury in pediatric brain tumor (BT) patients are poorly understood and biomarkers predicting cognitive deficits are lacking. Resting state functional MRI (rsfMRI) can evaluate large-scale brain networks to provide insight into neural changes that follow diagnosis and treatment. This project evaluated functional brain network segregation in pediatric BT patients treated with proton beam radiation therapy (PBRT). METHODS: rsfMRI scans were acquired from 21 pediatric patients (5 female, 16 male) with any brain tumor diagnosis treated with PBRT. Data were processed to reduce contamination, and correlation matrices were generated using all gray matter voxels. Brain network segregation (BNS) was measured and compared to 139 age-matched controls. Analysis included comparison of BNS in association systems (comprised of default mode, frontoparietal, dorsal attention, language, salience, and cingulo-opercular networks) and somatosensory systems (including auditory, visual, and somatomotor networks). Patient and clinical factors were evaluated for relationships with BNS. Patients underwent cognitive testing utilizing the NIH Toolbox Cognitive Domain (NIH-TCD). RESULTS: Median age at PBRT was 10 years (range 2.2-17.9). PBRT volume was whole brain in 10 and conformal in 11. rsfMRI occurred at a median of 2.9 years (range 1.0-5.6) after PBRT. Average BNS of association systems was significantly lower in patients than in controls (t= -8.1, p&amp;lt;10-10), but there was no significant difference in BNS of somatosensory systems (p=0.4). There was a trend towards worse BNS in association systems in patients &amp;lt;10 years old at PBRT (p=0.07). Patients demonstrated deficits in cognitive testing as assessed by the NIH-TCD; however, there were no significant relationships between score and network segregation. CONCLUSION: Pediatric BT patients treated with PBRT demonstrated normal BNS in somatosensory systems. However, BNS of association systems, which control high-level cognitive functions including social cognition, attention, and memory formation, was significantly decreased in BT patients treated with PBRT.
A phase II study of durvalumab (MEDI4736) immediately after completion of chemoradiotherapy in unresectable stage III non–small cell lung cancer: TORG1937 (DATE study).
Authors: Shinji Nakamichi, Kaoru Kubota, Toshihiro Misumi, Shuji Murakami, Tetsuro Kondo, Isamu Okamoto, Koichi Minato, Daijiro Harada, Kazutoshi Isobe, Hidetoshi Itani, Saori Takata, Hiroshi Wakui, Yuki Misumi, Satoshi Ikeda, Tetsuhiko Asao, Takeo Inoue, Shinobu Hosokawa, Yumiko Kobayashi, Yuichi Takiguchi, Hiroaki Okamoto
Journal: Journal of Clinical Oncology (2022)

8536 Background: Concurrent chemoradiotherapy followed by durvalumab maintenance for up to 12 months is the standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC). However, the best timing of starting durvalumab after completion of chemoradiation has not been identified. Progression-free survival (PFS) and overall survival (OS) were better in the subgroup of patients administered durvalumab within 14 days after last radiation to randomization according to the PACIFIC study (Antonia SJ, et al. 2017, 2018 NEJM). Methods: This study was a prospective, single-arm, multicenter, phase II clinical trial. Eligibility criteria included patients with unresectable stage III NSCLC, ECOG PS 0-1, age &lt; 75 years old. Patients who did not have disease progression after definitive concurrent chemoradiotherapy (CCRT) (chemotherapy: 2 cycles of platinum-based doublet chemotherapy, radiotherapy: 60 Gy/30 Fr) received durvalumab (10 mg/kg, every 2 weeks for up to 12 months) from the next day (allowed up to 5 days) after last radiation. The primary endpoint was 1-year PFS rate from registration assessed by an independent review committee. The planned sample size was 47 with a threshold value of 50% based on results of the PACIFIC study, an expected value of 63%, one-sided alpha of 20% and power of 80% in 1-year PFS rate. Results: From January 2020 to August 2020, 50 patients were enrolled from 16 institutions and 47 patients were evaluable for efficacy and safety. Forty-two patients received durvalumab maintenance therapy. Patient characteristics were: male/female 41/6; median age 65 (range 42-75); ECOG PS 0/1 28/19; IIIA/IIIB/IIIC 19/21/7. The 1-year PFS rate from registration was 75.0% (60% CI: 69.0 to 80.0). The 1-year OS rate from registration was 97.7% (95%CI: 84.6 to 99.7). ORR, median PFS and median OS were 78.7%, 14.2 months (95%CI: 13.4 to not reached (NR)) and NR, respectively. Grade 3/4 adverse events were pneumonitis (4.3%), neutropenia (44.7%), febrile neutropenia (4.3%). There was no treatment-related death. Conclusions: Our study met the primary endpoint. Durvalumab can be safely administered immediately after completion of CCRT for patients with unresectable stage III NSCLC, no additional or unexpected toxicity occurred as a reference to the PACIFIC study. Clinical trial information: jRCTs031190117.
Real-world outcomes of immunotherapy regimens in first line non small cell lung cancer in lebanese patients.
Authors: Lewis Nasr, Saada Diab, Ahmad Ghoche, Intissar Yehia, Fadi louis Nasr
Journal: Journal of Clinical Oncology (2022)

e18741 Background: Immunotherapy provides improved treatment efficacy and survival in NSCLC patients. This is well established from clinical trials. However, the effectiveness of immunotherapy in real world practice is not well assessed. We aimed to characterize real-world outcomes for patients with NSCLC treated with 1L I-O in Lebanon. Methods: Patients aged ≥18 years with confirmed metastatic NSCLC who received either 1L I-O monotherapy or single-agent I-O combined with chemotherapy on or after January 1, 2014. Primary objectives were to examine overall survival (OS) and real-world progression-free survival. Multivariable analysis were made on correlation of different factors and survival. Results: among 135 patients, Median age at diagnosis was 68 years Most patients received chemotherapy alone as first line(54%), 18.3 % received immunotherapy and 27.8% received the combination treatment of chemotherapy and immunotherapy. Median PFS 1 was 7.7, 14, 11.1 months for chemotherapy, immunotherapy and chemo-immunotherapy respectively (p = 0.062). Median OS was 22.9 months (CI 95%, 17.7-28.1) with no significant correlation with treatment type (p = 0.85) multivariate analysis showed that having PDL levels between 1 and 49 (HRa = 0.15) and ≥50 (HRa = 0.12) compared to &lt; 1 were significantly associated with longer PFS period, whereas having squamous (HRa = 3.45) and other (HRa = 27.36) type of cancer compared to adenocarcinoma was significantly associated with shorter PFS period. (HRa = 3.28) was significantly associated with lower overall survival period (p = 0.10).Concerning adverse effects, rash was the most frequent (14%) followed by pneumonitis (12.2%). Conclusions: In real world practice, IO was well tolerated in lebanese patients. Patients with high (≥50) and intermediate (between 1 and 49) tumor programmed death ligand 1 (PD-L1) expression demonstrated longer median OS vs those with low expression. We hypothesize that bone metastasis impairs immunotherapy efficacy.
IMMU-15. The immunologic context of pediatric central nervous system malignancies and identification of pan-histology immunomodulatory targets
Authors: Robert Galvin, Julia Nikrad, Tyler Jubenville, Danielle Maeser, Robert Gruener, Sampreeti Jena, Christopher Moertel, David Largaspaeda, R Stephanie Huang
Journal: Neuro-Oncology (2022)

Abstract Central nervous system tumors account for the most childhood cancer mortality. Immunotherapies have made major contributions to treat adult cancers, but application of immunotherapy for childhood brain tumors has been limited, in part due to the unique CNS microenvironment and mechanisms of immune escape in this context. To investigate the immunologic context, we query the transcriptomic profile of ~700 primary brain tumors released by the Children’s Brain Tumor Network. An immune subtype classification from The Cancer Genome Atlas project reveals that 81% of high-grade tumors across molecular subtypes are characterized by an immunosuppressive phenotype (C4) while an inflammatory phenotype (C3) is more common in low-grade lesions (p&amp;lt;0.001). Adjusting for histologic grade and extent of resection, C4 associates with worse overall (OS) and progression-free survival (PFS) in this cohort (HR 3.1, p=0.008 and 1.6, p=0.03 respectively). Deconvolution of the transcriptome reveals that relative to C3, C4 tumors have decreased T-cell signature, OR 0.4 (0.2–0.8), and increased macrophage and tumor-proliferation signature (OR 2.0, 1.3–3.3, and 3.1, 2.3–4.2, respectively). In contrast to C3 tumors, T-cell signature in C4 tumors adversely impacts survival and correlates with multiple immunosuppressive genes and cytokines. Among them, the immune checkpoint CD276 has the highest associated impact on survival in C4 tumors (HR of log increase is 1.9, p&amp;lt;0.001). Additionally, high-grade lesions have suppressed expression of antigen-presenting genes. EZH2 is implicated in downregulating antigen presentation and is found to be significantly upregulated in all high-grade lesions in this cohort. Treatment with the EZH1/2 inhibitor valemetostat resulted in upregulation of antigen-presenting genes and tissue differentiation pathways across three murine syngeneic models, one modeling diffuse midline glioma and two embryonal models. Future in-vivo studies with genetic and chemical modification of immunomodulatory genes of interest aim to identify immunotherapeutic targets with potential for broad applicability in pediatric neuro-oncology.
Immunological Interaction of HLA-DPB1 and Proteinase 3 in ANCA Vasculitis is Associated with Clinical Disease Activity
Authors: Dhruti P. Chen, Elizabeth A. McInnis, Eveline Y. Wu, Katherine G. Stember, Susan L. Hogan, Yichun Hu, Candace D. Henderson, Lauren N. Blazek, Simon Mallal, Edita Karosiene, Bjoern Peters, John Sidney, Eddie A. James, William W. Kwok, J. Charles Jennette, Dominic J. Ciavatta, Ronald J. Falk, Meghan E. Free
Journal: Journal of the American Society of Nephrology (2022)

PR3-ANCA vasculitis has a genetic association with HLA-DPB1. We explored immunologic and clinical features related to the interaction of HLA-DPB1*04:01 with a strongly binding PR3 peptide epitope (PR3225-239).Patients with ANCA vasculitis with active disease and disease in remission were followed longitudinally. Peripheral blood mononuclear cells from patients and healthy controls with HLA-DPB1*04:01 were tested for HLA-DPB1*04:01 expression and interaction with a PR3 peptide identified via in silico and in vitro assays. Tetramers (HLA/peptide multimers) identified autoreactive T cells in vitro. RESULTS: The HLA-DPB1*04:01 genotype was associated with risk of relapse in PR3-ANCA (HR for relapse 2.06; 95% CI, 1.01 to 4.20) but not in myeloperoxidase (MPO)-ANCA or the combined cohort. In silico predictions of HLA and PR3 peptide interactions demonstrated strong affinity between ATRLFPDFFTRVALY (PR3225-239) and HLA-DPB1*04:01 that was confirmed by in vitro competitive binding studies. The interaction was tested in ex vivo flow cytometry studies of labeled peptide and HLA-DPB1*04:01-expressing cells. We demonstrated PR3225-239 specific autoreactive T cells using synthetic HLA multimers (tetramers). Patients in long-term remission off therapy had autoantigenic peptide and HLA interaction comparable to that of healthy volunteers.The risk allele HLA-DPB1*04:01 has been associated with PR3-ANCA, but its immunopathologic role was unclear. These studies demonstrate that HLA-DPB1*04:01 and PR3225-239 initiate an immune response. Autoreactive T cells specifically recognized PR3225-239 presented by HLA-DPB1*04:01. Although larger studies should validate these findings, the pathobiology may explain the observed increased risk of relapse in our cohort. Moreover, lack of HLA and autoantigen interaction observed during long-term remission signals immunologic nonresponsiveness.
HGG-44. Unraveling and Targeting the stem-regulatory network driving invasion in Diffuse hemispheric glioma, H3G34-mutant
Authors: Alessandro Palma, Roberta Ferretti, Giulia Pericoli, Marsha Pellegrino, Lucia Lisa Petrilli, Valeria Molinari, Jessica K R Boult, Lynn Bierke, Andrea Carai, Angela Mastronuzzi, Simon P Robinson, Angel Montero Carcaboso, Chris Jones, Franco Locatelli, Emmanuel de Billy, Maria Vinci
Journal: Neuro-Oncology (2022)

Abstract Diffuse hemispheric glioma H3G34-mutant (DHG-G34) is a pediatric-type high-grade glioma affecting children and young adults. Despite surgery and radio/chemotherapy, patients have a dismal prognosis. The intratumoural heterogeneity and the high infiltrative nature of DHG-G34 cells limit the development of effective therapies. Analysing single-cell RNA sequencing data from a publicly available dataset, we identified a large and distinct sub-population of cells displaying high stem and low differentiation marker expression levels. Gene ontology analyses revealed a gene signature related to cell migration/invasion. This observation is supported by our data on in vitro 3D invasion assay and in vivo orthotopic xenograft models, showing that DHG-G34 disseminating cells are characterised by high expression level of the stem-cell marker NESTIN and low expression level of the differentiation marker GFAP. Following these findings, we developed high-throughput cell-based assays with the aim to screen a library of 1300 FDA-approved compounds and identify drugs able to induce DHG-G34 cell differentiation and inhibit their invasive phenotype. The screen, a co-immunofluorescence assay for NESTIN and GFAP, followed by dose response assays on 3D growth and 3D invasion, led to the identification of 3 FDA-approved drugs, the MEK inhibitor Cobimetinib and 2 HMG-CoA reductase inhibitors, Rosuvastatin and Pitavastatin. These 3 drugs potently induced cell differentiation (decreased Nestin and increased GFAP expression) and inhibited invasion with minimal effect on the proliferation of our DHG-G34 cell line. We are currently extending these findings to additional patient-derived DHG cell lines and we are using these drugs and different omics and imaging technologies to characterize the regulatory networks associated to DHG-G34 stemness, (de)-differentiation and invasiveness. Our work may lead to the identification of new therapeutic approaches for targeting the stem/invasive properties of these aggressive diseases.
The theory of tumor ecosystem
Authors: Xueman Chen, Erwei Song
Journal: Cancer Communications (2022)

Abstract Cancer cells can be conceived as “living organisms” interacting with cellular or non‐cellular components in the host internal environment, not only the local tumor microenvironment but also the distant organ niches, as well as the immune, nervous and endocrine systems, to construct a self‐sustainable tumor ecosystem. With increasing evidence for the systemic tumor‐host interplay, we predict that a new era of cancer therapy targeting the ecosystemic vulnerability of human malignancies has come. Revolving around the tumor ecosystem scoped as different hierarchies of primary, regional, distal and systemic onco‐spheres, we comprehensively review the tumor‐host interaction among cancer cells and their local microenvironment, distant organ niches, immune, nervous and endocrine systems, highlighting material and energy flow with tumor ecological homeostasis as an internal driving force. We also substantiate the knowledge of visualizing, modelling and subtyping this dynamically intertwined network with recent technological advances, and discuss ecologically rational strategies for more effective cancer therapies.